This is a revised application for a K23 Mentored Patient-Oriented Research Career Development Award entitled: """"""""Modeling Cholinergic Modulation of fMRI Memory Networks in Aging &MCI"""""""". This research proposal aims to combine functional MRI (fMRI), memory testing, medications that affect acetylcholine (ACh), and mathematical modeling to investigate the effects of aging, amnestic-mild cognitive impairment (MCI - a precursor of Alzheimer's disease, AD), and cholinergic changes on critical brain regions and their interactions during the learning of face-name pairs. Learning and remembering the names of new individuals we encounter is a particularly difficult demand in daily life and the most common memory complaint of older individuals visiting memory clinics. Meanwhile, deficits in central cholinergic function occur in the process of normal aging and become increasingly apparent in clinical AD, yet the exact nature and effects of these changes on memory systems in MCI and early AD remain elusive. Acetylcholinesterase inhibitors (AChEl) produce modest overall benefits in AD but their effects in MCI are less clear. The primary research questions in this proposal are: 1) What are the cognitive and fMRI correlates of cholinergic modulation in youth, aging and MCI? 2) Can they sensitively differentiate aging and MCI? 3) Can they serve as biomarkers to predict the 2-year clinical course of MCI? 4) Will combining pharmacological cognitive fMRI with modeling methods increase the ability to delineate the nature, functional integrity and compensatory reserve of memory systems in aging and MCI? As part of the proposed research, the candidate seeks training in: 1) fMRI analysis and modeling techniques; 2) cognitive neruoscience of aging and memory impairment;and 3) ethical clinical research methods. The proposed plan will foster the candidate's development into an independent physician-scientist using cognitive neuroscience, modeling, and pharmacological methods to study the functional neuro-anatomy, physiology, and chemisty of memory changes in aging and MCI. MCI is a condition that will affect increasing numbers of older adults and is thougth to represent a very early manifestation of AD. As more effective treatments are developed, it is an essential matter of public health to diagnose and treat AD at the earliest. This proposal works towards this goal.
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